Abstract ? Project Summary Cognition Therapeutics Inc.?s (Cogrx) mission is to develop effective therapeutics for Alzheimer?s disease (AD). Oligomers of the brain protein Amyloid beta 42 (A?Os) have been identified as toxic components that are involved with disease progression. Cognition has identified a subset of sigma-2 receptor binding modulators that displaces A?Os from synaptic receptor sites and clears them into the cerebral spinal fluid (CSF). These compounds accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma-2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then rapidly cleared into the CSF (within hours). As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). CogRx has discovered two CNS drug-like lead series of A?O displacing compounds. Analogs from these series displace oligomers from neurons and completely block A?O-induced membrane trafficking changes and synapse loss in vitro. Members of these series are highly brain-penetrant and completely block oligomer- induced memory deficits in Alzheimer?s disease mouse models. Drug candidate CT1812 from Series 1 is progressing through Phase I clinical trials with an open IND in the US. We have now turned our attention to identifying new candidates to provide a measure of risk mitigation in the event that our current candidate falters due to unforeseen issues. Cognition and Temple University identified a new lead series of sigma-2 receptor binding modulators, originally discovered at Temple University, that block A?O-induced membrane trafficking changes. The feasibility of medicinal chemistry optimization was established in a Phase I STTR project. This Phase II proposal seeks to further optimize this new series by synthesis and testing of new analogs designed to improve pharmacological and ADME properties. This proposal will allow us to expand our portfolio of sigma- 2 receptor binding modulators with the goal of identifying orally efficacious candidates for further development as therapeutics for AD.